Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC-derived air-liquid interface model.
Alveolar Epithelial Cells
/ metabolism
Biomarkers
/ metabolism
Cell Differentiation
/ physiology
Cells, Cultured
Cytokines
/ metabolism
Humans
Idiopathic Pulmonary Fibrosis
/ metabolism
Induced Pluripotent Stem Cells
/ metabolism
Lung
/ metabolism
Pulmonary Alveoli
/ metabolism
Stem Cells
/ metabolism
IPF
alveolar epithelium
bronchiolization
induced pluripotent stem cells
pro-fibrotic milieu
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
21
11
2019
revised:
29
02
2020
accepted:
26
03
2020
pubmed:
17
4
2020
medline:
20
1
2021
entrez:
17
4
2020
Statut:
ppublish
Résumé
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause that is characterized by progressive fibrotic lung remodeling. An abnormal emergence of airway epithelial-like cells within the alveolar compartments of the lung, herein termed bronchiolization, is often observed in IPF. However, the origin of this dysfunctional distal lung epithelium remains unknown due to a lack of suitable human model systems. In this study, we established a human induced pluripotent stem cell (iPSC)-derived air-liquid interface (ALI) model of alveolar epithelial type II (ATII)-like cell differentiation that allows us to investigate alveolar epithelial progenitor cell differentiation in vitro. We treated this system with an IPF-relevant cocktail (IPF-RC) to mimic the pro-fibrotic cytokine milieu present in IPF lungs. Stimulation with IPF-RC during differentiation increases secretion of IPF biomarkers and RNA sequencing (RNA-seq) of these cultures reveals significant overlap with human IPF patient data. IPF-RC treatment further impairs ATII differentiation by driving a shift toward an airway epithelial-like expression signature, providing evidence that a pro-fibrotic cytokine environment can influence the proximo-distal differentiation pattern of human lung epithelial cells. In conclusion, we show for the first time, the establishment of a human model system that recapitulates aspects of IPF-associated bronchiolization of the lung epithelium in vitro.
Identifiants
pubmed: 32297676
doi: 10.1096/fj.201902926R
doi:
Substances chimiques
Biomarkers
0
Cytokines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7825-7846Subventions
Organisme : MRF
ID : MRF_MRF-091-0001-RG-GARNE
Pays : United Kingdom
Informations de copyright
© 2020 Boehringer Ingelheim Pharma GmbH & Co. KG. The FASEB journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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